PTTG and PBF repress the human sodium iodide symporter

Abstract

The ability of the thyroid to accumulate iodide provides the basis for radioiodine ablation of differentiated thyroid cancers and their metastases. Most thyroid tumours exhibit reduced iodide uptake, although the mechanisms accounting for this remain poorly understood. Pituitary tumour transforming gene (PTTG) is a proto-oncogene implicated in the pathogenesis of thyroid tumours. We now show that PTTG and its binding factor PBF repress expression of sodium iodide symporter (NIS) messenger RNA (mRNA), and inhibit iodide uptake. This process is mediated at least in part through fibroblast growth factor-2. In detailed studies of the NIS promoter in rat FRTL-5 cells, PTTG and PBF demonstrated specific inhibition of promoter activity via the human upstream enhancer element (hNUE). Within this B1 kb element, a complex PAX8-upstream stimulating factor 1 (USF1) response element proved critical both to basal promoter activity and to PTTG and PBF repression of NIS. In particular, repression by PTTG was contingent upon the USF1, but not the PAX8, site. Finally, in human primary thyroid cells, PTTG and PBF similarly repressed the NIS promoter via hNUE. Taken together, our data suggest that the reported overexpression of PTTG and PBF in differentiated thyroid cancer has profound implications for activity of the NIS gene, and hence significantly impacts upon the efficacy of radioiodine treatment.

Expression and function of the novel proto-oncogene PBF in thyroid cancer: a new target for augmenting radioiodine uptake

“…Within this model, PTTG-mediated repression of iodide uptake was significantly abrogated by FGF-2 antibody treatment, suggesting that it is influenced by FGF-2 secretion, whereas repression by PBF remained unchanged, suggesting that this is independent of FGF-2 (Boelaert et al 2007).…”

“…The initial observation that PTTG may be involved in the regulation of iodide uptake led us to investigate the possibility of a similar role for PBF. We subsequently found that in our series of thyroid cancers, which demonstrated increased PTTG and PBF expression, NIS expression was significantly reduced compared with normal thyroid (Boelaert et al 2007), showing a significant negative correlation with both PTTG and PBF expression (K Boelaert, VE Smith, JA Franklyn, CJ McCabe unpublished data). Reduced NIS expression was also associated with early tumour recurrence and nodal involvement, further emphasising the importance of NIS activity in patient outcome (Boelaert et al 2007).…”

“…A significant reduction in NIS mRNA expression and 125 I uptake following PTTG overexpression was replicated in vitro in primary human thyroid cultures (Boelaert et al 2007; Fig. 2A).…”

“…Interestingly, PBF overexpression also resulted in significantly reduced NIS expression and iodide uptake. Further, the greatest reduction in iodide uptake seen was a synergistic inhibition following the co-transfection of both PBF and PTTG cDNA (Boelaert et al 2007). …”

“…Promoter studies identified the human NIS upstream enhancer (hNUE) as the element responsible for mediating the repression of NIS by PTTG and PBF using both FRTL-5 cells and human primary thyroid cultures (Boelaert et al 2007; Fig. 2B).…”